Zhang Yunwen, Chen Ruixiang, Hu Qimiao, Wang Jie, Nie Huimin, Yin Chengyu, Li Yuanyuan, Wei Huina, Liu Boyu, Tai Yan, Fang Junfan, Shao Xiaomei, Jin Xiaoqing, Fang Jianqiao, Liu Boyi
Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China.
Centre for Neurodevelopmental and Neurodegenerative Diseases, The Brain Cognition and Brain Disease Institute of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
Front Cell Neurosci. 2022 May 25;16:826777. doi: 10.3389/fncel.2022.826777. eCollection 2022.
Complex regional pain syndrome type-I (CRPS-I) is a chronic neurological disorder that results in severe pain and affects patients' life quality. Conventional therapies usually lack effectiveness. Electroacupuncture (EA) is an effective physical therapy for relieving CRPS-I pain. However, the mechanism underlying EA-induced analgesia on CRPS-I still remain unknown. Spinal NLRP3 inflammasome was recently identified to contribute to pain and neuroinflammation in a rat model of CRPS-I by our group. Here, we aimed to study whether EA could inhibit spinal NLRP3 inflammasome activation, thus resulting in pain relief and attenuation of spinal neuroinflammation in the rat model of CRPS-I. We established the rat chronic post-ischemic pain (CPIP) model to mimic CRPS-I. CPIP rats developed remarkable mechanical allodynia that could be relieved by daily EA intervention. NLRP3 inflammasome was activated in spinal cord dorsal horn (SCDH) of CPIP rats, accompanied with over-production of pro-inflammatory cytokine IL-1β. Immunostaining revealed that the cellular distribution of NLRP3 was predominantly located in SCDH neurons. Pharmacological activation of NLRP3 inflammasome is sufficient to produce persistent mechanical allodynia in naïve animals, whereas blocking NLRP3 inflammasome attenuates mechanical allodynia of CPIP rats. EA exclusively reduced NLRP3 overexpression in SCDH neurons and attenuated spinal glial cell over-activation in CPIP rats. EA-induced anti-allodynia with attenuation of spinal glial cell over-activation were all mimicked by intrathecal blocking NLRP3 inflammasome and reversed by activating NLRP3 inflammasome, respectively, through pharmacological methods. Finally, spinal blocking IL-1β attenuated mechanical allodynia and spinal glial cell over-activation in CPIP rats, resembling the effects of EA. In all, these results demonstrate that spinal NLRP3 inflammasome activation contributes to mechanical allodynia of the rat model of CRPS-I and EA ameliorates mechanical allodynia through inhibiting NLRP3 inflammasome activation in SCDH neurons. Our study further supports EA can be used as an effective treatment for CRPS-I.
Ⅰ型复杂性区域疼痛综合征（CRPS-Ⅰ）是一种慢性神经紊乱疾病，会导致严重疼痛并影响患者的生活质量。传统疗法通常效果不佳。电针（EA）是缓解CRPS-Ⅰ疼痛的一种有效物理疗法。然而，EA诱导CRPS-Ⅰ镇痛的机制仍不清楚。最近我们团队发现，在CRPS-Ⅰ大鼠模型中，脊髓NLRP3炎性小体与疼痛和神经炎症有关。在此，我们旨在研究EA是否能抑制脊髓NLRP3炎性小体的激活，从而缓解CRPS-Ⅰ大鼠模型的疼痛并减轻脊髓神经炎症。我们建立了大鼠慢性缺血后疼痛（CPIP）模型来模拟CRPS-Ⅰ。CPIP大鼠出现明显的机械性异常性疼痛，每日EA干预可缓解这种疼痛。CPIP大鼠脊髓背角（SCDH）中的NLRP3炎性小体被激活，同时促炎细胞因子IL-1β产生过量。免疫染色显示，NLRP3的细胞分布主要位于SCDH神经元中。药理学激活NLRP3炎性小体足以在未处理的动物中产生持续性机械性异常性疼痛，而阻断NLRP3炎性小体可减轻CPIP大鼠的机械性异常性疼痛。EA专门降低了SCDH神经元中NLRP3的过表达，并减轻了CPIP大鼠脊髓胶质细胞的过度激活。通过药理学方法，鞘内阻断NLRP3炎性小体模拟了EA诱导的抗异常性疼痛并减轻脊髓胶质细胞过度激活的作用，而激活NLRP3炎性小体则使其作用逆转。最后，脊髓阻断IL-1β减轻了CPIP大鼠的机械性异常性疼痛和脊髓胶质细胞过度激活，类似于EA的作用。总之，这些结果表明，脊髓NLRP3炎性小体激活导致CRPS-Ⅰ大鼠模型的机械性异常性疼痛，而EA通过抑制SCDH神经元中NLRP3炎性小体的激活来改善机械性异常性疼痛。我们的研究进一步支持EA可作为CRPS-Ⅰ的有效治疗方法。
